3,3-dimethylcyclohexylideneacetonitriles

ABSTRACT

This invention relates to an improved method for the preparation of three components of the boll weevil pheromone - Z and E-3,3dimethylcyclohexylideneacetaldehyde and Z-3,3dimethylcyclohexylidenethanol. A Wittig reagent prepared from diethyl cyanomethylphosphonate and base in a suitable solvent is used to convert 3,3-dimethylcyclohexanone to Z and E-3,3dimethylcyclohexylideneacetonitrile. The latter two compounds are converted to the corresponding aldehydes by reduction followed by in situ hydrolysis. These aldehydes represent two of the active components of the boll weevil sex pheromone. The stereochemistry of the nitrile intermediate resulting from the Wittig reaction can be controlled to a degree by altering solvent and base. Reduction and hydrolysis provide aldehydes stereochemically rich in a given isomer. Subsequent reduction of the aldehyde mixture provides a mixture of Z and E-3,3-dimethylcyclohexylidenethanols with the same isomer distribution as in the aldehyde precursor. Alternatively, isomers can be separated at the nitrile, aldehyde, or alcohol stage.

United States Patent i191 Babler [451 Dec. 3, i974 1 1 3,3-1D1M1ETHYLCYCLOHEX- YLIDENEACETONITRILES [76] Inventor: James Ill. Babler, I25 Callan,

Evanston, 111. 60602 [22] Filed: Oct. 13, 11972 [2]] Appl. No.1 297,421

[52] 11.8. CI. 260/464, 260/598, 260/617 R, 260/617 C [51] Int. Cl. C07c 121/48 [58] Field of Search 260/464 [56] References Cited UNITED STATES PATENTS 2,882,158 14/1959 Brooker et al... .l.; 260/464 X $251,874 5/1969 Strickland et a1 260/464 OTHER PUBLICATIONS Braude, et al., J. Chem. Soc., 1955, pp. 320-328.

Primary Examiner-Joseph PsBrust Attorney, Agent, or Firm-.lohn J; McDonnell ABSTRACT This invention relates to an improved method for the preparation of three components of the boll weevil pheromone Z and E-3,3-dimethylcyclohexylideneacetaldehyde and Z-3,3-dimethy1cyclohexylidenethanol. A Wittig reagent prepared from diethyl cyanomethylphosphonate and base in a suitable s01- vent is used to convert 3,3-dimethylcyclohexanone to Z and E-3,3-dimethylcyclohexylideneacetonitrile. The latter two compounds are converted to the corresponding aldehydes by reduction followed by in situ hydrolysis. These aldehydes represent two of the active components of the boll weevil sex pheromone. The stereochemistry of the nitrile intermediate resulting from the Wittig reaction can be controlled to a degree by altering solvent and base. Reduction and hydrolysis provide aldehydes stereochemically rich in a given isomer. Subsequent reduction of the aldehyde mixture provides a mixture of Z and E-3,3-dimethylcyclohexylidenethanols with the same isomer distribution as in the aldehyde precursor. Alternatively, isomers can be separated at the nitrile, aldehyde, or alcohol stage.

2 Claims, N0 Drawings 1 I 3 ,3 -DIMETHYLCYCLOHEXYLIDENEACETONI- TRILES Insect sex attractants (pheromones) are of considerable interest and economic importance in that they offer a nontoxic ecologically acceptable method of surveying and controlling insect populations. The compo- I nents of the pheromone emitted by the male boll weevil (Anthonomus grandis Boheman) are known to be terpenoids I, II, III and IV. (Tumlinson, et al., Science 166, 1012, 1969) Table 1, taken from Tumlinson (supra), indicates the effectiveness of various combination of] through IV in 'I. ll, IV

0.2 ml. of dichloromethane. The standards used were live male boll weevils or steam distillates that were equivalent in attractancy to live males.

Respective amounts Average (as) T Sample III I, II

I, III

I, IV II, III II, IV III, IV I, II, III ,0.l2

I, III, IV II, III, IV I, II, III, IV

Since III and IV are combined in equimolar quantities in the pheromone composition, it is evident that the ZE isomers do not need to be separated.

The object of this invention is to provide an improved method for the preparation of Z and E-3,3-dimethylcyclohexylideneacetaldehyde (III and IV). Mixtures of Z and E-3,3-dimethylcyclohexylidenethanol, which are rich in the Z isomer (II), are easily prepared in the context of the process of the present invention. Preparaattracting female boll weevils as compared to the naturally occurring pheromone. Response of female boll weevils in laboratory bioassay to optimum concentrations of compounds I, II, III and IV. The 178 equals net response to test sample divided by net response to a standard. The sample in each case consisted of the compound. or the indicated mixture of compounds in alkyl a CHE-OH no-cn Solvent Yield tion of the pure Z-3,3-dimethylcyclohexylidenethanol,

(II), is somewhat less efficient than preparation of the aldehyde mixture because of the necessity to separate isomers at some stage of the process.

These compounds have previously been prepared through laborious multistep processes by Tumlinson et. al., J. Org. Cherrn, 36, 2616 (I971). The present invention relates to a novelprocess for preparing terpenoids II, III, and IV. This process (Scheme I) is characterized by simplicity, high yield, and some degree of stereochemical control.

2') (a1kyl) A1 H 3) hydrolysis Reduction Yield H CHO 0H0 5 The first step of this process involves the reaction between 3,3-dimethylcyclohexanone and a Wittig reagent, prepared from a dialkyl cyanomethylphosphonate, in a solvent containing a base. Non-polar and polar solvents are used. Suitable non-polar solvents are benzene-pentane mixtures and suitable polar solvents are alcohols, such as ethanol and tertiary-butyl alcohol, dimethylformamide (DMF) anad dimethylsulfoxide (DMSO). Among operative bases are methyl lithium, sodium hydride, alkali metal alkoxides and tetraalkyl ammonium hydroxides. The preferred base/solvent system is sodium hydride in a polar solvent such as dimethylsulfoxide or dimethylformamide. This combination of base and solvent is preferred since it provides an excess of the Z-3,B-dimethylcyclohexylideneacetonitrile which, in turn, is required for the preparation, by subsequent steps of mixtures of alcohols rich in Z 3,3- dimethylcyclohexylidenethanol, II.

Table 2 shows the E and Z isomer distribution of 3,3- dimethylcyclohexylideneacetonitrile as a function of base and solvent.

TABLE 2 Z-isomer E-isomer Base Solvent 28 72 CH Li C l-l 50 50 NaH 9:1 c H -pentane 45 55 NaOC H CH CH OH 50 S0 NaOC(CH3)J (CH -,COH 65 35 I NaH DMF or DMSO The second step involves the reduction of the E and Z nitriles to E and Z imines followed by hydrolysis to the corresponding aldehydes. Alkyl substituted metal hydrides are the preferred reducing agents and diisobutylaluminum hydride is the most preferred. The resulting Z and E-3 ,3-dimethylcyclohexylideneacetaldehydes are present in the same ratio as that of the E and Z nitrile precursors. Standard reducing agents convert the aldehyde mixture to E and Z alcohols. Sodium borohydride performs this conversion quantitatively.

When the Wittig reaction is conducted in dimethylformamide, using sodium hydride as the base, the 3,3- dimethylcyclohexylideneacetonitriles are present in a Z/E ratio of 65/35. This mixture of nitriles is converted to Z-3,3-dimethylcyclohexylidenethanol containing the E isomer by the steps indicated above and the Z isomer is purified by standard separation techniques such as fractional distillation, vapor phase chromatography, or column chromatography. Alternatively, the Z and E- 3,3-dimethylcyclohexylideneacetonitrile isomers are separated prior to the nitrile reduction, hydrolysis, and aldehyde reduction steps. It is not necessary to purify each component since it is the mixture of I, II, 111, and IV which forms the effective pheromone. This invention therefore presents an improved method for the preparation of three of the active components of the boll weevil pheromone. The key intermediate in this process,Z-3,3-dimethylcyclohexylideneacetonitrile is an antagonist for prostaglandin E and bradykinin, in contrast to cyclohexylideneacetonitrile (Brande and Wheeler, J. Chem. Soc, 321, 1955) which is an antagonist for prostaglandin E but not for bradykinin.

The bradykinin-antagonist properties of the compounds of the present invention are evidenced by results of the following test. Two Charles River female rats weighing 240-280 grams are treated on each of two successive days with diethylstilbesterol in order to induce a state of estrus. On the third day the animals are sacrificed and the uteri are removed. A 10 mm. section is taken from one of the uteri and suspended in a tissue bath containing 1.9 ml. of Tyrodes solution, prepared as described by Barnes and Eltherington, Drug Dosage in Laboratory Animals, p. 261, University of California Press, Berkeley, California (1964). The tissue bath is surrounded bya water jacket maintained at a constant temperature of 30C. The concentration of bradykinin in the tissue bath is then gradually increased by successive additions of bradykinin dissolved in Tyrodes solution. The bradykinin solution concentration is defined as the pD, which is the log of the reciprocal of the concentration expressed in mg./ml. At each of the selected bradykinin concentrations, contraction of the uterus is measured in mm. by means of an E & M Physiograph used together with an Isotonic Myograph Transducer and Detecting Head. After completion of those measurements the tissue is rinsed nine times over a period of 9' minutes with fresh Tyrodes solution. The last rinse is kept in the bath and 100 mcg. of the test compound dissolved or suspended in 0.1 ml. of Tyrodes solution is injected into the bath, which consists of 1.9 ml. of Tyrodes solution. The contractions at each concentration are measured as before and are compared with the control values, i.e., those obtained in the absence of the test compound. The identical procedure is then carried out with the 10 mm. section of the uterus taken from the second animal. A compound is considered active either if it inhibits by at least 10 percent the maximum bradykinin-induced contraction or if it causes an increase of at least 0.3 pD unit in bradykinin concentration required to effect percent of the maximum contraction.

The PGE antagonist properties of the compounds of the present invention are evidenced by results of the following test. The test procedure is substantially that described by J. H. Sanner, Arch; int. Pharmacodyn., 180 (1), 46 (1969). Female albino guinea pigs weighing 200-500 g. are sacrificed by cervical dislocation and-the ileum is quickly removed and placed in modified Tyrodes solution containing one-half the usual amount of magnesium ions. Segments of ileum, about test suspension is kept in constant contact with the tissue for the remainder of the experiment except for brief periods to drain the bath in preparation for rinsing with fresh test suspension. Three more contractions are elicited to each agonist in the presence of the test compound without interrupting the time sequence. The last 2 sets of treated responses are compared with the 2 sets of control responses. The first set of treated responses is not used for comparisons, being used only to maintain the timed sequence of injections during the period allowed for the tissue to become equilibrated with the antagonist. The compound is rated active if the mean of contractions produced by any agonist is reduced 75 percent or more by the test compound.

EXAMPLE 1 In an inert atmosphere, 1.89 parts of diethyl cyanomethylphosphonate in 5 parts by volume of dimethylformamide are added to a cold (-l5) suspension of 0.25 part of sodium hydride in 5 parts by volume of dimethylformamide. This mixture is brought to room temperature and a solution of 1.26 parts of 3,S-dimethylcyclohexanone in parts by volume of dimethylformamide is added to the above base solution. After 1 hour, 50 parts by volume of water are added and the product is separated from the reaction mixture by extraction with pentane. The product is purifled by fractional distillation and the isomers are separated by vapor phase chromatography on a 12 foot column packed with 10 percent tetracyanoethylated pentaerythritol on Aeropak 30, 80/ 100 mesh at 120. The Z-3,3-dimethylcyclohexylideneacetonitrile has an nmr spectrum which is characterized by a 6 proton geminal methyl proton absorption at 0.99 8 and a single viny-l proton absorption at 5.12 8. The corresponding E-3,3- dimethylcyclohexylideneacetonitrile isomer absorptions are, respectively, 0.935 8 and 5.01 8. The formulas are:

H NC

EXAMPLE 2 To a solution of 1.35 parts of a mixture of E and Z- 3,3dimethylcyclohexyliderieacetonitrile in parts by volume 'of benzene is added 1.42 parts of diisobutylaluminum hydride. After 4 hours, 120 parts by volume of saturated ammonium chloride solution is added and the product is isolated by ether extraction. The ether extracts are washed successively with 5 percent hydrochloric acid, saturated sodium bicarbonate, 10 percent sodium chloride solution. The ether extracts are then dried over anhydrous magnesium sulfate and filtered. The ether is removed by evaporation at reduced pressure to provide E and Z-3,3-dimethylcyclohexylendenacetaldehyde. The formulas are:

EXAMPLE 3:

1.5 parts of 65/35 mixture of Z/E stereoisoniers of 3,3-dimethylcyclohexylideneacetaldehyde is added to 30 parts by volume of absolute ethanol containing 0.2 parts of sodium borohydride. After 1 hour, the reaction mixture is poured into 150 parts by volume of water and the aqueous layer is then saturated with sodium chloride. The product is isolated by extraction with penta riefTh pentane extracts are washed with 10 per cent sodium chloride and dried over magnesium sulfate. Removal of the solvent by evaporation at reduced pressure provides a 65/35 mixture of the Z/E stereoisomers of 3.3-dimethylcyclohexylidenethanol. The formulas are:

EXAMPLE 4- What is claimed is: l. The mixture of Z and E-3.,3-dimethylcyclohex- I ylideneacetonitrile containing 28 to 65 percent Z-3,3-

dimethylcyclohexylideneacetonitrile. 

1. THE MIXTURE OF Z AND E-3,3DIMETHYLCYCLOHEXYLACETONITRILE CONTAINING 28 TO 65 PERCENT Z-3,3-DIMETHYLCYCLOHEXYLIDENEACETONITRILE.
 2. Z-3,3-dimethylcyclohexylideneacetonitrile. 